METHODE DE PREPARATION D'ESTERS D'ACIDES HYDROXYCYCLOHEXANECARBOXYLIQUES SUBSTITUES

PROCESS FOR THE PREPARATION OF BASIC ESTERS OF SUBSTITUTED HYDROXYCYCLOHEXANECARBOXYLIC ACIDS

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
The yield of compounds having the general formula:
<IMG> (I)
wherein R represents
<IMG> . or <IMG>
in the process comprising reacting a substituted hydroxy-
cyclohexanecarboxylic acid with an aminoisopropyl chloride
is highly improved by heating the reaction mixture to 160 to
240°C for at least 3 hours, and distilling the resulting
product under reduced pressure. This process enables the
content of the undesired isomer to be reduced to less than
1-1.5%.

Revendications

The embodiments of the invention in which an exclu-
sive property or privilege is claimed are defined as follows:-
1. A process for the preparation of basic esters of
substituted hydroxycyclohexanecarboxylic acids having the
general formula:
<IMG> (I)
in which R represents
<IMG> , or <IMG>
wherein a substituted hydroxycyclohexanecarboxylic acid of
the formula:
<IMG>
in which R has the aforesaid meaning, is reacted with an
aminoisopropyl hydrochloride of the formula:
<IMG>
to produce a mixture of isomers comprising the desired
basic ester having formula (I) and the isomer thereof having
the formula:
<IMG>

characterized in that the reaction mixture, after isolation,
is subjected to thermal isomerization by heating for at least
3 hours from about room temperature to a temperature of between
160°C and 240°C, and the thus heated mixture is fractionally
distilled under reduced pressure at a temperature not less
than that of said heating.
2. A process according to claim 1, characterized in
that said heating takes place by heating from room temperature
to about 180°C during about 6 hours and the fractional distil-
lation takes place at about 210°C.
3. A process according to claim 1, characterized in
that said heating is carried out by heating from room temper-
ature to a temperature between about 220-230°C during 3 hours
and the fractional distillation is carried out at about 240°C.
4. A process according to claims 1 to 3, character-
ized in that said compound of formula (I) is 2-(diethylamino)-
1-methylethyl-cis-1-hydroxy-[bicyclohexyl]-2-carboxylate.
5. A process according to claims 1 to 3, character-
ized in that said compound of formula (I) is 2-(diethylamino)-
1-methylethyl-cis-2-hydroxy-2-phenyl-cyclohexanecarboxylate.

Description

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The present invention relates to the preparation of
basic esters of substituted hydroxycyclohexanecarboxylic acids,
having the following general formula:
R OH / 2 5
COO CH-CH2-N (l)
CH3
wherein R represents
, or ~
More specifically, the present invention relates to an
- improved process for the preparation of 2-(diethylamino)-1-
methylethyl-_is-l-hydroxy-[bicyclohexyl]-2 carboxylate, and of
2-(dlethylamino)-1-methylethyl-cis-2-hydroxy-2-phenyl-cyclo-
- hexanecarboxylate.
m e esters of formula I, which are known for their
antl-spastic activity, are part of a family of basic esters,
disclosed in U.K~ Patent Specification No. 1,167,386 and in
German Patent No. 1,618,624.
According to the known prior art, these esters are
prepared by a general method comprising reacting the potassium
salt of a substituted hydroxycyclohexane carboxylic acid with
an aminoalky] chloride:
R~OH / ~ ~ H
C00K +Cl-CH2-cH2-N ~--~~ COOCH2-C~2-N ~
There are also known two alternative methods, having
limited practical importance, due to the poor yields of the
i 20 desired pxoduct. One of these methods consists in the reac-
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tion of the potassi~ salt of a substituted hydroxycyclo-
hexanecarboxylic acid with an alkylene di-halide and subse-
quent reaction of the alkylhalogenated ester with a secondary
amine. me second method is based on the chlorination, under
mild conditions, of a substituted hydro.~ycyclohexanecarboxy-
lic acid and subsequent reaction of the related acylchloride
with an amino alcohol.
Among all these methods, the only one of effective
interest from the industrial point of view is the first men-
tioned process. A detailed descrlption of this method, interm~ of one of the esters, is given in example IV of the
U.K. Patent Specification No. 1,167,336, alrea~y referred to.
By applying this method to the compounds of the pre~
sent invention, it is possible to obtain a product fulfilling
the analytical requirements, provided that the raw product, of
oily nature, is subjected to two subsequent distillation steps,
instead of only one, or to a fractionation by rectification,
these operations certainly affecting the yield.
In the case of the subject compounds ~as represented
by formula 1), during the reaction of cis-l-hydroxy-[bicyclo-
hexyl]-2-carboxylic acid or of cls-2-hydroxyphenyl-cyclohexane-
carboxylic acid and l-diethylamino-2-chloropropane in the pre-
sence of an acceptor of hydrogen chloride (such as, for in~-
tance, K2CO3, NaOH, KOCH3, NaOCH3, etc.), two products are al-
ways formed, which, for the sake of convenience, are identi-
fied as A and B, according to the following scheme:
.; '1 .
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C2H5
R OH
,X, ,COO CH-CH2-N
~,, CH3 C2 H5
R OH ~C~H5 HCl A
X COOH 1- Cl- OEI-CH2-N acceptor ¦
~J CH3 C2H5 R OH /C2H5
X COO- CH2- CH-~
J CH3 C~I5
~ B
wherein R ls ~ or - O
his is due to the fact that, as it is well known,
diethylamino-2-chloropropane does react in the cyclic form:
C~I2 CH CH3
~''' . /
., ~
in which the breakage of the bond i9 possihle ei.ther in the
position (a), to give place to the product A, and in the po-
sition (b), giving thus place to the product B.
~y varying the solvent and the reaction temperature
, . . .
: different proportion~ of product A and o~ product B are obtain-
~: : ed, but the amount of the lmdesired isomer B cannot be lowered
.below 28-30%, when R = C6HLl, and below 16-17%, when R = C6H5, .
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respectively. The influence o~ the solvent and of the temper-
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ature on the composition of the reaction product is shown by
the following results, relating to the reactions carried out
with cis-l-hydroxy-[bicyclohexyl]-2-carboxylic acid:
- in anhydrous toluene, using K2C03 as the hydrogen acceptor
Product A 53.5%~
)25C
Product B 46.5% J
Product A 57.0% ~
100 C
Product B 43.0%
- in anhydrous dimethyl formamide, using K2C03 as the hydrogen
acceptor
Product A 63.0% 1
25C
Product B 37.0% J
- in isopropanol, using potassium methylate as the hydrogen
acceptor
Product A 64.5% ~
; ~25C
Product B 35.5% J
Product A 72.0%~
~ 80C
: Product B 28.0% ¦
j~ - in isopropanol. using K3C03 as the hydrogen acceptor
.
Product A 70.0% ~
80C
Product B 30.0% J
The separation of the product A from the product B
as obtained by the above described reaction, can be carried
out by fract.ional distillation.
Of course, the yield of the process, in terms of the
product A, which is the des.ired one, is always remarkably
reduced in comparison with the theoretical value.
e main purpose of the present invention is therefore
that of solving the above mentioned problem, which purpose is
attained by a~process characterized in that the reaction mixture,
comprising product A and product B, is heated to a temperature
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between 160C and 240C for a time of at least 3 hours, and
then the mixture is fractionally distilled at a temperature
not lower than that of the said heating step.
In fact, it has been assessed that, by the process of
the present invention, the final product has a highly reduced
content of product B which, under optimum conditions, is not
higher and often lower than 1%, w~len R = C6Hll, and lower
than 1.5%, when R = C6H5.
me advantages of the process according to the pre-
sent invention are per se readily appreciated: instead ofbeing compelled to separate from the reaction mixture the un-
; desired isomer, and moreover through a difficult operation
which causes the ylelds to be reduced, the reaction mixture
undergoes a further treatment step by which the yi~ld of
the desired compound is almost the theoretical one.
According to the practice of the process according tothe present invention, the mixture of compounds A and B, after
; the normal isolation steps,`is heated to a temperature of bet-
ween 160 and 240C, preferably to a temperature not less than
180C, for a period of ~ime of at least 3 hours, the upper li~
; mit being the time beyond which the desired compound A is de-
composed. In fact, it has been found that the heating temper~
ature and the heating time are inversely proportional, w~ereby
yields close to 100% of the theoretical value are obtained
both by heating at 180C for six hours and subsequent distilla-
tion at the same temperature, and by heating at 220-230~C for
3 hours and subsequent fractional distillation at 230-240C.
The following examples, having only illustrative but
not limitative meaning, disclose in details the process of
the present invention.
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EXAMPLE 1
200 g of ci3-l-hydroxy-[bicyclohexyl~-2-carboxylic
acid, dissolved in 1000 mls of isopropyl alcohol are supple-
; mented with 188 g of anhydrous potassium carbonate~ The
mixture is heated to reflux (82C~ and,by maintaining this
temperature, 164 g of 1-diethylamino-2-chloropropane hydro-
chloride, dissolved in 500 mls of isopropyl alcohol, are
added.
When the addition is completed, the reaction mixture
is maintained under reflux for 7 hours~
The reaction mixture is cooled and the salts (KC1 and
; KHCO3) are filtered, the isopropylic solution, containing
70% of product A and 30% of product B is subjected to thermal
isomerization in the following manner. The solvent is evapo-
rated and the residue (300 g) is dissolved in ethyl ether, the
ethereal solution is extracted at 0C with diluted hydrogen
chloride, the thus separated aqueous phase is made definitely
alkaline at 0C with diluted sodium hydroxide, and then
~ repeatedly extracted with ethyl ether. The ethereal extracts
~ are repeatedly waished with water until neutral and the solvent
is evaporated. The residue (275 g), comprising 70% of pro
duct A and 30% of product ~ is gradually heated from 25C to
180 C during 6 hours, and then distilled under reduced pres-
sure (G,1-0.2 mm~Ig) in an oil bath at 210C.
There are obtained 267 g of 2-(diethylamino)-1-methyl-
ethyl-cls-l)hydroxy-[bicyclohexyl~-2-carboxylate, with a con~
tent of isomer B less than 0.5%~
EXAMPLE 2
Example 1 is repeated until the residue of 275 g is
obtained, containing 70% of product A and 30% o~ product B.
The mixture is gradually heated from 25C to
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220-230C during three hour~ and then distilled under reduced
pressure (0.1-0.2 mmHg) in an oil bath at 230-240C.
There are obtained 267 g of product AJ with a content
of product B less than 1%.
EXAMPLE 3
200 g of cis-2-hydroxy-2-phenyl-cyclohexa~e carboxy-
lic acid, dissolved in 1000 mls of isopropyl alcohol, are sup-
plemented with 188 g of anhydrous potassium carbonate. The
mixture is heated to reflux (82C) and by maintaining the same
temp~rature, there are added 164 g of 1-diethylamino-2-chloro- ~-
`~; propane hydrochloride, dissolved in 500 mls of isopropyl al-
cohol. When the addition is completed, the reaction mixture
is maintained under reflux for 7 hours. The raaction mixture
is then cooled and the salts (KCl and ICHC03) are filtered, the
isopropylic solution containing 83.5% of product A and 16.5%
~ of product B is subjected to thermal isomerization in the -fol-. lowing manner.
The solvent is evaporated and the residue (296 g) is
dissolved in ethyl ether, the ethereal solution is extracted
at 0C with diluted HCl, the thus separated aq~teous phase is
made definitely alkaline at 0C with diluted sodium hydroxide
and then repeatedly extracted with ethyl ether. I~le ethereal
extracts are repeatedly washed with water until neutral and
the solvent is evaporated.
The residue (288 g), comprising 83.5~ of product A
and 16. ~ of Product B is gradually heated from 25C to
180C in 6 hours and then distilled under vacuum (0.1-0.2
mm~g) in an oil bath at about 210C. ~here are obtained 260 g
of product A having a content of product B less than 1.5%.
Similar results are obtained by heating from 25C
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to 200C and then distilling the mixture under reduced pres-
sure ~0.2 mmHg~ in an oil bath at abou~ 2~0-230C.
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